title: Determinism and stochasticity during maturation of the zebrafish antibody repertoire.
abstract: It is thought that the adaptive immune system of immature organisms follows a more deterministic program of antibody creation than is found in adults. We used high-throughput sequencing to characterize the diversifying antibody repertoire in zebrafish over five developmental time points. We found that the immune system begins in a highly stereotyped state with preferential use of a small number of V (variable) D (diverse) J (joining) gene segment combinations, but that this stereotypy decreases dramatically as the zebrafish mature, with many of the top VDJ combinations observed in 2-wk-old zebrafish virtually disappearing by 1 mo. However, we discovered that, in the primary repertoire, there are strong correlations in VDJ use that increase with zebrafish maturity, suggesting that VDJ recombination involves a level of deterministic programming that is unexpected. This stereotypy is masked by the complex diversification processes of antibody maturation; the variation and lack of correlation in full repertoires between individuals appears to be derived from randomness in clonal expansion during the affinity maturation process. These data provide a window into the mechanisms of VDJ recombination and diversity creation and allow us to better understand how the adaptive immune system achieves diversity.
authors.affiliation: Department of Bioengineering, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Jiang
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Weinstein
authors.forename: Lolita
authors.initials: L
authors.lastname: Penland
authors.forename: Richard A
authors.initials: RA
authors.lastname: White
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Fisher
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D000818:Animals; D000906:Antibodies / Q000235:genetics*; D000916:Antibody Diversity; D050440:Immunoglobulin Subunits / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D013269:Stochastic Processes; D050441:VDJ Exons; D015027:Zebrafish / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; D050440:Immunoglobulin Subunits; D007135:Immunoglobulin Variable Region